1. Field of the Invention
The invention describes phenazopyridine covalently attached to various conjugates. These compounds and compositions are useful for providing increased (oral) bioavailability with reduced side effects.
2. Related Art
Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties. However, the citation of any reference herein should not be construed as an admission that such reference is available as prior art to the present application.
Phenazopyridine is an analgesic compound indicated for urinary tract pain, burning, irritation, and discomfort, as well as urgent and frequent urination caused by urinary tract infections, surgery, injury, or examination procedures. Phenazopyridine, while an effective analgesic, carries with it a foreboding side effect profile, with nausea, vomiting, and general GI upset being the most severe events. In an effort to improve the side effect profile and expand the use of phenazopyridine, it is proposed to pursue the development of a prodrug compound that results in the formation of the active drug following transport across the gastrointestinal epithelium.
Phenazopyridine or 2,6-pyridinediamine, 3-(phenylazo), monochloride (CAS number 94-78-0) is an azo dye that exerts topical analgesic or local anesthetic action on the urinary tract mucosa and provides symptomatic relief of pain, burning, urgency, frequency and other discomforts arising from irritation of lower urinary tract caused by infections, trauma, surgery, endoscopic procedures or use of catheters. Phenazopyridine has been marketed since 1925 and since 1951 has had a dual status of prescription and over-the-counter (OTC).
Phenazopyridine is marketed as single agent 100 and 200 mg tablets under a number of brand names including Nefrecil, Phenazodine, Pyridiate, Pyridium, Sedural, Uricalm, Uropyrine, Urodine, and Urogesic. Single agent OTC medications include Azo-Gesic, Azo-Standard, and Uristat (95 mg tablets), ReAzo (97 mg tablets), and URIRelief and Baridium (97.2 mg tablets). Phenazopyridine is available as a combined prescription with sulfisoxazole or sulfamethoxazole/trimethoprim and as Phenazopyridine plus in combination with hyosciamine and secbarbitol.
The usual adult dosage is 100-200 mg three times daily after meals for no more than two days and 12 mg/kg/day in three divided doses after meals in children for no more than two days. The pharmacological mechanism of the analgesic effect of phenazopyridine is unknown.
Phenazopyridine is absorbed from the gastrointestinal tract following oral administration. Although the absolute bioavailability in humans has not been determined it is apparently poorly absorbed with the highest prescribed dose of 200 mg yielding maximum plasma levels between 10 and 20 ng/mL. Phenazopyridine is rapidly excreted up to 65% unchanged in urine with approximately 90% of a single dose cleared within 24 hours. Metabolites include aniline, N-acetyl-p-aminophenol (NAPA or acetaminophen) and p-amino phenol. Aniline may contribute to the analgesic effect of orally administered phenazopyridine in the urinary tract mucosa.
Adverse reactions associated with therapeutic doses of phenazopyridine include headache, rash pruritus, gastrointestinal disturbances (nausea, vomiting, and diarrhea), orange to red urine discoloration and staining of soft contact lenses. In cases of insufficient renal clearance phenazopyridine can tinge skin, sclera or fluids yellow due to accumulation of the drug. Methemaglobenemia, hemolytic anemia, renal and hepatic toxicity have been reported, usually at overdose levels. Anaphylactoid reactions have been reported.
Phenazopyridine and the metabolite aniline can cause oxidative stress within red blood cells by conversion of hemoglobin to methemaglobin. Patients with glucose-6-phosphate dehydrogenase deficiency may be predisposed to hemolytic anemia. Phenazopyridine should not be administered to patients with impaired renal function. Exceeding the recommended dose may lead to increased serum levels and toxic reactions. Methemaglobinemia generally follows excessive acute overdose. Considering the long history and fairly widespread use of phenazopyridine, reports of serious toxicity are relatively uncommon.
Long term (2 years) administration of phenazopyridine hydrochloride induced adenomas and adenocarcinomas in the large intestine of rats and lifetime administration caused hepatocellular adenomas and carcinomas in female mice. Phenazopyridine has been shown to be mutagenic in bacteria and mutagenic and clastogenic in mammalian cells. In one limited epidemiological study of 2,214 patients who received phenazopyridine hydrochloride there was no observed increase in the occurrence of any type of cancer over a minimum period of 3 years. Current phenazopyridine product labeling indicates: “Long term administration of phenazopyridine hydrochloride has induced neoplasia in rats (large intestine) and mice (liver). Although no association between phenazopyridine hydrochloride and human neoplasia has been reported, adequate epidemiological studies along these lines have not been conducted.”
Reproduction studies at doses up to 50 mg/kg/day or 110 mg/kg/day in rats and 39 mg/kg/day in rabbits showed no effects on fertility or embryo-fetal development. Phenazopyridine is currently classified in pregnancy category B. There have been no adequate and well controlled studies of phenazopyridine exposure in pregnant women. Surveillance studies have been reported with no link of phenazopyridine use to congenital defects. The Collaborative Perinatal Project monitored 50,282 mother-child pairs with 1,109 exposures recorded during pregnancy and 219 exposures during the first trimester. No association was found with major or minor malformations or individual defects. Surveillance of 229,101 Michigan Medicaid patents identified 469 phenazopyridine exposures during the first trimester. No data was obtained to indicate any association of the drug with abnormalities.
The acute toxicity LD50 for phenazopyridine has been reported as 472 mg/kg (oral) and 200 (i.p.) in rats; and 180 mg/kg (i.p.) in mice. Adequate safety pharmacology and repeat dose nonclinical toxicology studies have not been performed for phenazopyridine.